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Sterol Homeostasis Requires Regulated Degradation of Squalene

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Sterol Homeostasis Requires Regulated Degradation of Squalene RESEARCH ARTICLE elife.elifesciences.org Sterol homeostasis requires regulated degradation of squalene monooxygenase by the ubiquitin ligase Doa10/Teb4 Ombretta Foresti1,2, Annamaria Ruggiano1,2, Hans K Hannibal-Bach3, Christer S Ejsing3, Pedro Carvalho1,2* 1Cell and Developmental Biology Programme, Center for Genomic Regulation (CRG), Barcelona, Spain; 2Universitat Pompeu Fabra, Barcelona, Spain; 3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark Abstract Sterol homeostasis is essential for the function of cellular membranes and requires feedback inhibition of HMGR, a rate-limiting enzyme of the mevalonate pathway. As HMGR acts at the beginning of the pathway, its regulation affects the synthesis of sterols and of other essential mevalonate-derived metabolites, such as ubiquinone or dolichol. Here, we describe a novel, evolutionarily conserved feedback system operating at a sterol-specific step of the mevalonate pathway. This involves the sterol-dependent degradation of squalene monooxygenase mediated by the yeast Doa10 or mammalian Teb4, a ubiquitin ligase implicated in a branch of the endoplasmic reticulum (ER)-associated protein degradation (ERAD) pathway. Since the other branch of ERAD is required for HMGR regulation, our results reveal a fundamental role for ERAD in sterol homeostasis, with the two branches of this pathway acting together to control sterol biosynthesis at different levels and thereby allowing independent regulation of multiple products of the mevalonate pathway. DOI: 10.7554/eLife.00953.001 *For correspondence: pedro. [email protected] Introduction Sterols, such as cholesterol in animals or ergosterol in yeast, are essential components of cellular Competing interests: The authors membranes and their concentration to a large extent determines many of the membrane properties, declare that no competing interests exist. such as fluidity and rigidity. Therefore, cells evolved sophisticated mechanisms to precisely regulate their sterol levels (Goldstein et al., 2006; Brown and Goldstein, 2009). These are critical not only for Funding: See page 15 adjusting membrane properties to diverse cellular environments but also for preventing the accumulation Received: 16 May 2013 of free sterols, which is toxic both to individual cells and to whole organisms (Goldstein et al., 2006; Accepted: 18 June 2013 Espenshade and Hughes, 2007; Maxfield and van Meer, 2010). Published: 23 July 2013 The regulation of cellular sterol levels occurs primarily during their biosynthesis in the endoplasmic reticulum (ER) by the mevalonate pathway (Espenshade and Hughes, 2007; Brown and Goldstein, Reviewing editor: Michael S Brown, University of Texas 2009). This highly conserved pathway produces isoprenoids, precursors not only for sterols but also Southwestern Medical School, for other essential molecules such as dolichol or ubiquinone (Figure 1A; Goldstein and Brown, 1990). United States While a constant supply of these molecules is required, cells must avoid overaccumulation of sterols, a balance that is achieved by a number of feedback systems operating at the transcription, translation, Copyright Foresti et al. This and post-translational levels. Remarkably, decades of work demonstrated that many of these homeostatic article is distributed under the control systems converge on the regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), terms of the Creative Commons Attribution License, which an enzyme involved in an early and rate-limiting step of the mevalonate pathway (Brown and Goldstein, permits unrestricted use and 2009; Burg and Espenshade, 2011). redistribution provided that the A key mechanism in sterol homeostasis involves the proteasomal degradation of HMGR in a original author and source are sterol-dependent manner (Burg and Espenshade, 2011). In fact, an increase in sterol biosynthetic credited. intermediates, such as geranylgeranyl pyrophosphate in yeast and lanosterol or its immediate product Foresti et al. eLife 2013;2:e00953. DOI: 10.7554/eLife.00953 1 of 17 Research article Biochemistry | Cell biology eLife digest All cells are enclosed by a membrane that is made up of fatty molecules called lipids and is studded with proteins. This membrane allows cells to detect and react to outside events. Since external conditions, such as temperature, can vary dramatically, membranes need to be able to adjust their properties. For example, lipids become more fluid as the temperature rises, so membranes respond to heat stress by incorporating molecules called sterols to increase their rigidity. In fact, sterols have profound effects on membrane properties and are essential to regulate a number of cellular processes. But high levels of sterols can become toxic, so it is essential that they are carefully controlled. Sterols, such as ergosterol in yeast or cholesterol in mammals, are synthesized in a tightly regulated multi-step process; some of the early steps in sterol production also make common building blocks for other key molecules in the cell. A mechanism to control sterol levels is the regulated destruction of an enzyme that carries out an early step of their synthesis. This occurs via one branch of the ER-associated degradation (ERAD) pathway, which also destroys non-functional proteins. Now, Foresti et al. have found that sterol synthesis is also regulated by another branch of the ERAD pathway. This second control point, which occurs later in the biosynthetic process, allows cells to regulate sterol levels independent of the other products of the pathway that are derived from the same preliminary compounds. In yeast, the two ERAD branches are directed by Hrd1 and Doa10. These are both ubiquitin ligases— proteins that attach a tag called ubiquitin to other proteins, thus labeling them for recycling by the proteasome (essentially a waste-disposal complex in the cell). To identify the proteins that are tagged by Doa10, Foresti et al. compared protein levels in strains lacking Doa10 with those in wild type yeast. Unexpectedly, the enzyme Erg1, which helps to synthesize ergosterol, was more abundant in cells lacking Doa10. Foresti et al. found that Doa10 tagged Erg1 for destruction when levels of the building blocks of ergosterol rose inside the cell. These ergosterol intermediates are toxic to yeast, which converts them into less harmful molecules known as sterol esters using the proteins Are1/2. When the DOA10 or ARE1/2 genes were deleted, these intermediates were more abundant; strikingly, they became even more prevalent when all three genes were knocked out in the same strain. In contrast, blocking the other ERAD branch by deleting HRD1 did not cause ergosterol intermediates to accumulate, nor did it exacerbate the effects of ARE1/2 knockout. When combined with previous findings, these results provide evidence that the different branches of the ERAD pathway regulate ergosterol synthesis at distinct steps. The same mechanism is observed in human cells when high levels of cholesterol are detected. By identifying parallel routes to control sterol levels, this work reinforces the importance of membrane integrity to life. DOI: 10.7554/eLife.00953.002 24,25-dihydrolanosterol in mammals, strongly accelerates the degradation of HMGR, thereby lowering the flux through the mevalonate pathway. Both in yeast and in mammals, the targeting of HMGR to the proteasome for degradation is mediated by a branch of the ER-associated protein degradation (or ERAD) pathway, which is primarily studied for its role in the elimination of misfolded ER proteins (Smith et al., 2011; Brodsky, 2012). Importantly, ERAD factors involved in the recognition of misfolded ER proteins are not required for HMGR degradation. Instead specific chaperones called Insigs, in the presence of the right sterol signal, regulate the interaction of HMGR with the central ERAD components, a ubiquitin ligase complex in the ER membrane, called Hrd1 in yeast and Gp78 in mammals (Hampton et al., 1996; Bays et al., 2001; Sever et al., 2003; Flury et al., 2005; Song et al., 2005b). The Hrd1/ Gp78-dependent ubiquitination of HMGR leads to its membrane extraction, facilitated by the Cdc48/ p97 ATPase, and release in the cytoplasm for degradation by the proteasome. In mammalian cells, a second ER-bound ubiquitin ligase, Trc8, can also promote the sterol-dependent degradation of HMGR (Jo et al., 2011a). Other branches of ERAD have never been implicated in sterol homeostasis. Here, we report a novel role of ERAD in the regulation of sterol biosynthesis. A screen for substrates of the ERAD ubiquitin ligase Doa10 identified the squalene monooxygenase Erg1, an enzyme required for a sterol-specific step of the mevalonate pathway inSaccharomyces cerevisiae. We show that Doa10-dependent degradation of Erg1 is regulated by the levels of lanosterol and that, together Foresti et al. eLife 2013;2:e00953. DOI: 10.7554/eLife.00953 2 of 17 Research article Biochemistry | Cell biology with sterol esterification, it is essential for preventing the accumulation of toxic sterol intermediates. Moreover, in mammalian cells, sterol-dependent degradation of squalene monooxygenase requires the Doa10 homologue Teb4. Altogether, our findings reveal an evolutionarily conserved, central role of ERAD in sterol homeostasis. Results Erg1 is a substrate of the Doa10 complex To identify novel substrates of the ERAD ubiquitin ligase Doa10 (Swanson et al., 2001), we used SILAC (Stable Isotope Labeling by Amino acids in Culture) labeling followed by quantitative
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